G-quadruplex DNA in senescence of the neurovascular unit

项目摘要 神经血管单位（NVU）是由内皮细胞组成的功能性结构，其被血管内皮细胞包围。 细胞外基质、神经元、星形胶质细胞和周细胞。NVU能够调节局部脑血 血流和营养输送到脑组织。随着老化，NVU的结构弱化发生，这也是 与炎症信号和运输缺陷有关。重要的是，目前还不清楚神经元， 星形胶质细胞、周细胞和内皮细胞在NVU中经历衰老，以及是否存在差异 在健康NVU老化和阿尔茨海默病（AD）中的NVU之间的衰老途径中。 G-四链体（G4）是由四条DNA链形成的非典型DNA二级结构， 多次注射鸟嘌呤G4在DNA重组、复制和调控中起着重要作用。 转录。在我们的数据中，我们证明了老年小鼠的大脑样本比老年小鼠的大脑样本含有更多的G4。 年轻的老鼠我们发现，用小分子G4稳定剂治疗的小鼠出现认知障碍， 加速大脑衰老使用异时联体小鼠模型，我们还表明，G4 s水平 与年龄匹配的同种联体小鼠相比，老年联体小鼠大脑中的 存在返老还童的因素，可以扭转随着年龄的增长G4的升高。古老的副离子的影响 对年轻伴侣的影响更为明显（年轻人中G4更多），这表明 老化因素重要的是，在AD小鼠模型中，我们证明了G4在大脑中是稳定的， 在淀粉样蛋白沉积发生之前。我们假设这些证据的汇合点是 衰老机制因此，拟议研究的主要目的是研究G4相关的 NVU中的细胞衰老，老化和AD。在目标1中，我们将比较NVU中不同细胞类型的G4。 在目标2中，我们将确定G4是否优先在最脆弱的大脑区域的NVU中积累 神经退化在目标3中，我们将研究外周因子CXCL 10如何促进NVU的G4 衰老G4 s可能是一种新的途径，可以靶向减轻细胞凋亡的有害影响。 大脑的衰老

Project Summary The neurovascular unit (NVU) is a functional structure that consists of endothelial cells, surrounded by an extracellular matrix, neurons, astrocytes, and pericytes. The NVU enables regulation of regional cerebral blood flow and nutrient delivery to the brain tissue. With aging, a structural weakening of the NVU occurs, which is also associated with inflammatory signaling and transport deficiencies. Critically, it is not clear how neurons, astrocytes, pericytes, and endothelial cells undergo senescence in the NVU, and whether there are differences in senescence pathways between healthy NVU aging and NVU in Alzheimer's diseases (AD). The G-quadruplex (G4) is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G4s play important roles in DNA recombination, replication, and regulation of transcription. In our data, we demonstrated that brain samples from aged mice contain more G4s than that of young mice. We showed that mice treated with a small-molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Using a heterochronic parabiosis mouse model, we also showed that the levels of G4s are decreased in the brain of old parabiont, compared to the age-matched iso-parabiotic mice, implicating presence of rejuvenating factors that can reverse the elevation of G4s with aging. The effect of the old parabiont on the young partner is more pronounced (more G4s in the young), suggesting a strong negative influence of aging factors. Importantly, in a mouse model of AD, we demonstrated that G4s are stabilized in the brains, well before the deposition of amyloid occurs. We hypothesize that these converging lines of evidence point at а mechanism of senescence. Thus, the primary objective of the proposed studies is to investigate G4-associated cellular senescence in the NVU, in aging and AD. In Aim 1, we will compare G4s across cell types in the NVU. In Aim 2, we will determine whether G4s preferentially accumulate in the NVUs of brain regions most vulnerable to neurodegeneration. In Aim 3, we will investigate how a peripheral factor, CXCL10, contributes to NVU's G4 senescence. G4s might be a novel pathway that can be targeted to mitigate the detrimental effects of cellular senescence in the brain.